Metabolic disease, including obesity, diabetes and atherosclerosis, is the leading cause of mortality in industrialized nations. It is estimated that over one-third of the United States population is obese and these individuals are at risk for developing diabetes and atherosclerosis. These disorders are responsible for over 500,000 deaths in the United States each year. The growing incidence of this problem has led to intense interest in identifying new molecular targets and new pharmacologic agents to treat and/or prevent these disorders.
Orphan nuclear receptors provide an example of an important class of molecular targets for the treatment of various diseases. Nuclear receptors are ligand-dependent transcription factors that regulate gene expression in response to small-molecule ligands. The orphan receptor ERRα (Estrogen-Related Receptor α) is known to be a regulator of lipid homeostasis. For example, mice lacking ERRα are lean and are resistant to developing obesity when challenged with a high-fat diet. See Luo, J., Sladek, R., Carrier, J., Bader, J. A., Richard, D. et al., Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha, Mol Cell Biol 2003, 23, 7947-7956. ERRα is expressed in tissues with a high capacity for β-oxidation of fatty acids including the heart, kidneys, brown adipose tissue and skeletal muscle. See Giguere, V., To ERR in the estrogen pathway, Trends Endocrinol Metab. 2002, 13, 220-225. ERRα expression is stimulated by the coactivator PGC-1α; see Schreiber, S. N., Knutti, D., Brogli, K., Uhlmann, T., Kralli, A., The transcriptional coactivator PGC-1 regulates the expression and activity of the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha), J Biol Chem 2003, 278, 9013-9018, and both proteins form a complex that stimulates the expression of genes involved in mitochondrial fatty acid oxidation (medium-chain acylcoenzyme A dehydrogenase, see Huss, J. M., Kopp, R. P., Kelly, D. P., Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-alpha and -gamma, Identification of novel leucine-rich interaction motif within PGC-1alpha, J Biol Chem 2002, 277, 40265-40274, peroxisome proliferator activated receptor α, see Huss, J. M., Torra, I. P., Staels, B.; Giguere, V., Kelly, D. P., Estrogen-related receptor {alpha} directs peroxisome proliferator-activated receptor {alpha} signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle, Mol Cell Biol 2004, 24, 9079-9091) and oxidative phosphorylation. See Mootha, V. K., Handschin, C., Arlow, D., Xie, X., St Pierre, J. et al., Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle, Proc Natl Acad Sci USA 2004, 101, 6570-6575; Schreiber, S. N., Emter, R., Hock, M. B., Knutti, D., Cardenas, J. et al., The estrogen related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)-induced mitochondrial biogenesis, Proc Natl Acad Sci USA 2004, 101, 6472-6477. ERRα has also been shown to regulate genes involved in intestinal lipid absorption and satiety signals (apolipoprotein A-IV, see Carrier, J. C., Deblois, G., Champigny, C., Levy, E., Giguere, V., Estrogen related receptor a (ERR a) is a transcriptional regulator of apolipoprotein A-IV and controls lipid handling in the intestine, J Biol Chem 2004) and vascular relaxation (endothelial nitricoxide synthase, see Sumi, D., Ignarro, L. J., Estrogen-related receptor alpha 1 up-regulates endothelial nitric oxide synthase expression, Proc Natl Acad Sci USA 2003, 100, 14451-14456).
Some forms of heart disease may be related to orphan ERR receptors. Acquired forms of heart failure are associated with switches in the substrate the heart uses for energy. In pressure-induced or volume overload-induced hypertrophy, mitochondrial fatty acid oxidative capacity is reduced and the heart then utilizes glucose as an an energy source (see Huss, J. M., and Kelly, D. P., Nuclear Receptor Signaling and Cadiac Energetics, Circulation Research, 2004, 95:568-578). The ERRa/PGC-1a complex is known to activate mitochondrial biogenesis and increase fatty acid oxidation (see Sladek, R., Bader, J-A., Giguere, V., The Orphan Nuclear Receptor Estrogen-Related Receptor alpha Is a Transcriptional Regulator of the Human Medium-Chain Acyl Coenzyme A Dehydrogenase Gene, Molecular and Cellular Biology, 1997, 17(9):5400-5409; Schreiber et al., supra; Mootha et al., supra; Willy, P. J., Murray, I. R., Qian, J., Busch, B. B., Stevens, W. C., Jr. et al., Regulation of PPARgamma coactivator 1alpha (PGC-1alpha) signaling by an estrogen-related receptor alpha (ERRalpha) ligand, Proc Natl Acad Sci USA, 2004, 101, 8912-8917; Lehman, J. J., and Kelly, D. P., Gene Regulatory Mechanisms Governing Energy Metabolism during Cardiac Hypertrophic Growth, Heart Failure Reviews, 2002, 7:175-185; Barger, P. M. and Kelly, D. P., Fatty Acid Utilization in the Hypertrophied and Failing Heart: Molecular Regulatory Mechanisms, American Journal of the Medical Sciences, 1999, 318:36; Sack M. N. and Kelly D. P., The energy substrate switch during development of heart failure: gene regulatory mechanisms, Int J Mol Med., January 1998; 1(1):17-24). Thus drugs that selectively activate ERRa/PGC-1a should have therapeutic benefits in heart disease by increasing Fatty acid oxidation.
Similarly, ERRa/PGC-1a activates expression of PDK4 thus decreasing glucose oxidation (see Wende, A. R., Huss, J. M., Schaeffer, P. J., Giguere, V. and Kelly, D. P., PGC-1alpha Coactivates PDK4 Gene Expression via the Orphan Nuclear Receptor ERRalpha: a Mechanism for Transcriptional Control of Muscle Glucose Metabolism, Molecular and Cellular Biology, 2005, 25(24):10684-10694). Thus drugs that selectively activate ERRa/PGC-1a should have additional therapeutic benefits in heart disease by decreasing glucose utilization.
Additionally, since activation of ERRa/PGC-1a complex is known to increase fatty acid oxidation (see Sladek et al., supra; Schreiber et al., supra; Mootha et al., supra; Willy, et al., supra), drugs that selectively activate ERRa/PGC-1a should be useful for treating obesity and diabetes.
Furthermore, since activation of ERRa/PGC-1a complex is known to decrease PEPCK expression (see Herzog, B., Cardenas, J., Hall, R. K., et al., Estrogen-related Receptor alpha Is a Repressor of Phosphoenolpyruvate Carboxykinase Gene Transcription, J. Biological Chemistry, 2006, 281(1):99-106) and since PEPCK is a rate-limiting step in glucose production in the liver, drugs that selectively activate ERRa/PGC-1a should decrease whole body glucose utilization and be further useful for the treatment of diabetes.
Because of the foregoing, it is desirable to develop compounds, and methods to synthesize said compounds, that can be used to modulate specific receptors in cells and in vivo including estrogen related receptors.